Overview

MS is thought to be an autoimmune disease even though no antigens are identified, with certainty, against which a disease-relevant autoimmune response might be directed. As with other autoimmune entities, there is a genetically determined propensity to develop the illness. The strongest positive genetic association is with the class II major histocompatibility complex (MHC) antigen, that is, the human leukocyte antigen (HLA)-DRB1*15:01. HLA-DR alleles present antigenic peptides to CD4⁺ T cells, pointing to a major disease-promoting role for CD4⁺ T cells in MS. In contrast, HLA-A*02:01 expression is reduced in MS, indicating a protective role for this, the most commonly expressed class I allele in humans. The less prevalent HLA-A*03:01 class I allele doubles risk for developing MS. HLA-A alleles present antigenic peptides to CD8⁺ T cells, indicating that CD8⁺ T-cell–mediated protection is suboptimal in MS. HLA-A*03:01 and HLA-DRB1*15:01 are independent risk factors. Genome-wide studies have identified some 50 additional minor genetic associations. Most have a role in immune system function with a major enrichment in cell surface receptor genes implicated in T-cell activation and proliferation. One third of identified genomic loci overlap with regions associated with one or more other autoimmune diseases.

The prevalence of MS can be as high as 1 in 500 in the overall population. Twenty percent of patients have a blood relative with the disease. In siblings and in children of an affected parent, concordance for MS is 1% to 3%, ruling out simple dominant, recessive, or sexlinked inheritance. Siblings share half their genes. Yet, even among identical twins sharing all their genes, MS concordance is only 25%, indicating that environmental factors have a major role in determining risk for MS.

Epstein-Barr virus (EBV) is acquired in adolescence or early adult years in developed countries, where MS is encountered frequently and where EBV often causes infectious mononucleosis; in less-developed countries, where MS is uncommon, EBV is usually acquired asymptomatically in early childhood. Unlike controls, at diagnosis all MS patients test positive for prior contact with EBV, and a history of frank infectious mononucleosis (always before disease onset) is increased threefold over the general population. EBV is at present the leading candidate environmental trigger for propensity to develop MS. The presence of subnormal vitamin D levels is a possible additional putative environmental factor in MS. This vitamin is an inflammatory response inhibitor and an enhancer of regulatory T-cell function, coupled with the fact that MS is uncommon in regions with high sunlight exposure, the chief inducer of vitamin D synthesis.

Clinical Course. MS usually begins in young adults; peak age at first attack is 30 years, but onset can occur before age 10 years or after age 50 years. MS is two to three times as frequent in women. Eighty-five percent of patients present with a clinically isolated syndrome characterized by subacute loss of neurologic function that will usually worsen over a week or more, stabilize for a time, and eventually recover partially or, quite often, completely. Subsequently, after highly variable intervals, additional episodes, known as relapses, develop. Relapses, having finite spans of a few weeks, are followed by recovery of variable extent and duration. Periods of seeming disease quiescence occur with remissions lasting for months or years. These patients are referred to as having relapsing-remitting multiple sclerosis (RRMS). Symptoms and signs vary from one relapse to the next as additional sites of myelin loss accumulate within the CNS white matter. Sites of myelin loss are called plaques; their locations determine symptoms.

After some years, the character of MS can change. Relapses diminish in frequency, ultimately cease, and are replaced by slow but steady worsening of nervous system impairment referred to as secondary progressive MS (SPMS), distinguishing it from the 15% of cases in which a primary progressive course is present from symptom inception. Primary progressive MS (PPMS) usually begins later in life than RRMS; a female preponderance is less evident. The usual presentation is a slowly progressive myelopathy evolving into paraparesis or paraplegia.

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